In the discovery of new drugs, potential drug candidates are generated by identifying chemical compounds with desirable properties. These compounds are sometimes referred to as xe2x80x9clead compoundsxe2x80x9d. Once a lead compound is discovered, variants of the lead compound can be created and evaluated as potential drug candidates.
In order to reduce the time associated with discovering useful drug candidates, high throughput screening (HTS) methods are replacing conventional lead compound identification methods. High throughput screening methods use libraries containing large numbers of potentially desirable compounds. The compounds in the library are numerous and may be made by combinatorial chemistry processes. In a HTS process, the compounds are screened in one or more assays to identify those library members (particular chemical species or subclasses) that display a desired characteristic activity. The compounds thus identified can serve as conventional xe2x80x9clead compoundsxe2x80x9d or they can be therapeutic.
Conventional HTS processes use multi-well plates having many wells. For example, a typical multi-well plate may have 96 wells. Each of the wells may contain a different liquid sample to be analyzed. Using a multi-well plate, a number of different liquid samples may be analyzed substantially simultaneously.
FIG. 1 shows a portion of a multi-well plate 10 having a base 17 and a rim 15. The rim 15 extends upward from the base 17 to define a well 16. A micropipette 11 is above the well 16 and dispenses a droplet comprising a liquid sample 13 into the well 16 and onto a sample surface 12. The droplet may have a surface xe2x80x9cSxe2x80x9d. While in the well 16, the rim 15 confines the liquid sample 13 to the sample surface 12 so that it may be analyzed.
It is desirable to reduce the volume of the wells in a multi-well plate to increase the density of the wells on the plate. By doing so, more wells can be present on the plate and more reactions can be analyzed substantially simultaneously. Also, as the volumes of the wells are reduced, the liquid sample volumes are reduced. Reducing the liquid sample volumes reduces the amount of reagents needed in the HTS process. By reducing the amount of reagents used, the costs of the HTS process can be reduced. Also, liquid samples such as samples of biological fluids (e.g., blood) are not always easy to obtain. It is desirable to minimize the amount of sample in an assay in the event that little sample is available.
While it is desirable to increase the density of the wells in a multi-well plate, the density of the wells is limited by the presence of the rims on the wells. The rims could be removed to permit the sample surfaces to be closer together and thus increase the density of the sample surfaces. However, by removing the rims, no physical barrier would be present between adjacent sample surfaces. This increases the likelihood that liquid samples on adjacent sample surfaces could intermix and contaminate each other.
Also, reducing the liquid sample volumes can be problematic. Decreasing the size of assays to volumes smaller than 1 microliter substantially increases the surface-to-volume ratio. Increasing the surface-to-volume ratio increases the likelihood that analytes or capture agents in the liquid sample will be altered, thus affecting any analysis or reaction using the analyte or capture agents. For example, proteins in a liquid sample are prone to denature at liquid/solid and liquid/air interfaces. When a liquid sample containing proteins is formed into a droplet, the droplet can have a high surface area relative to the amount of proteins in the droplet. If the proteins in the liquid sample come into contact with the liquid/air interface, the proteins may denature and become inactive. Furthermore, when the surface-to-volume ratio of a liquid sample increases, the likelihood that the liquid sample will evaporate also increases. Liquids with submicroliter volumes tend to evaporate rapidly when in contact with air. For example, many submicroliter volumes of liquid can evaporate within seconds to a few minutes. This makes it difficult to analyze or process such liquids. In addition, if the liquid samples contain proteins, the evaporation of the liquid components of the liquid samples can adversely affect (e.g., denature) the proteins.
Embodiments of the invention address these and other problems.
One embodiment of the invention is directed to a chip comprising: a) a base including a non-sample surface; and b) at least one structure, each structure comprising a pillar and a sample surface that is elevated with respect to the non-sample surface and is adapted to receive a sample from a dispenser.
Another embodiment of the invention is directed to an assembly adapted to process fluids, the assembly comprising: a) a dispenser comprising a body and at least one fluid channel defined in the body, each fluid channel being adapted to dispense a fluid on one or more of the sample surfaces; and b) a chip comprising (i) a base including a non-sample surface, and (ii) at least one structure, each structure comprising a pillar and a sample surface that is elevated with respect to the non-sample surface and is adapted to receive the fluid from the dispenser.
Another embodiment of the invention is directed to a method of processing fluids, the method comprising: a) supplying a fluid in a fluid channel in a dispenser; and b) dispensing the fluid on one or more structures on a base of a chip, wherein each structure comprises a pillar and includes a sample surface that is elevated with respect to the non-sample surface.
Another embodiment of the invention is directed to a method of processing fluids, the method comprising: a) supplying a plurality of liquids to respective fluid channels in a dispenser, wherein each of the fluid channels includes a passive valve and wherein the flow of each liquid in each fluid channel stops at the passive valve; b) aligning sample surfaces of a plurality of structures with the plurality of fluid channels, wherein each structure comprises a pillar; and c) contacting the sample surfaces and the liquids in the fluid channels while the sample surfaces are in or are positioned at the ends of the fluid channels.
Another embodiment of the invention is directed to a chip comprising: a) a base including a non-sample surface; and b) a plurality of structures in an array on the base, each structure comprising a pillar and a sample surface that is elevated with respect to the non-sample surface and is adapted to receive a sample from a dispenser to be processed or analyzed while the sample is on the sample surface.
Another embodiment of the invention is directed to an assembly adapted to process fluids, the assembly comprising: a) a chip comprising: i) a base including a non-sample surface; and ii) a plurality of structures in an array on the base, each structure comprising a pillar and a sample surface that is elevated with respect to the non-sample surface and is adapted to receive a sample to be processed or analyzed while the sample is on the sample surface; and b) a dispenser including a plurality of fluid channels, each fluid channel including a passive valve, wherein the dispenser dispenses liquid samples on the sample surfaces of the chip.
These and other embodiments are described in greater detail below.